This is a revised application for Project by Heaton. The aim of the Neurocognitive Project has been to examine neuropsychological (NP) outcomes associated with HIV infection in the context of methamphetamine (METH) dependence. We demonstrated that a history of METH dependence does confer increased risk for NP impairment in people with HIV. Patterns of NP impairments associated with both risk factors have been consistent with frontal-subcortical dysfunction. One third of METH users in our study population have chronic hepatitis C virus (HCV) infection. There is increasing evidence that HCV itself can be associated with brain dysfunction and NP impairment, even in patients without advanced liver disease. While treatment with combined interferon and ribavirin (IFN/RBV) results in sustained viral clearance in many HCV infected persons, it may also cause debilitating neuropsychiatric side effects that are reportedly more common in those with histories of substance use disorders. It is unknown whether successful HCV clearance and/or treatment-related neuropsychiatric side effects substantially affect longer term NP and everyday functioning outcomes. Project 1 will be composed of two studies. Study 1 is a cross-sectional evaluation of individuals in each of the three risk groups and their combinations, with the aim to determine the unique and combined neurobehavioral effects of METH, HIV, and HCV, and to link our observations to those of other Projects in the Program in an effort to delineate mechanisms of neuropathogenesis. Study 2 is an 18-month longitudinal investigation of HIV- individuals with history of METH dependence receiving IFN/RBV treatment for comorbid HCV infection. We will determine the incidence and clinical significance of neurobehavioral changes in relation to treatment side effects and success in achieving sustained viral clearance, and will collaborate with the Biomarkers Project in exploring pathophysiologic mechanisms of such changes. In this revision, in response to reviewer concerns regarding differences in variables among groups that could make interpretation difficult, we have expanded the HCV "only" risk group to include more persons with fewer confounds, and have revised our statistical approach to address imbalances in confounds more clearly.